Mycobacterium tuberculosis is readily transmitted from person to person. In the majority of healthy persons acquired immunity, consisting of T cells and macrophages, controls growth but does not eradicate M tuberculosis. Persistent organisms can result in clinical tuberculosis when host immunity fails. The interaction of T cells and macrophages is central to this protective immunity. Macrophages serve as antigen presenting cells for M tuberculosis specific T cell and as effector cell for controlling mycobacterial growth. The macrophage also is the primary target for M tuberculosis infection and site of mycobacterial persistence. Despite activation of CD4+, CD8+ and g/d T cells with potent effector functions against M tuberculosis, the organism survives and persists. Thus the outcome of the interaction between M tuberculosis and acquired immunity is determined by the balance between the host mononuclear phagocyte's ability to process and present M tuberculosis antigens to T cell subsets, and M. tuberculosis' ability to modulate and resist macrophage antigen processing function. The M tuberculosis phagosome becomes the critical macrophage organelle where this dynamic balance is expressed. Proposed studies build on experimental systems and new results obtained during the last cycle of support of AI-27243. The three specific aims are: 1. To determine the role of the M tuberculosis phagosome as site for antigen processing of antigens for MHC class I restricted CD4+ T cells, and to determine the role of cytokines (IFN-g, IL- 10, TGF-B) and mycobacterial constituents such as the 19 kDa lipoprotein to modulate antigen-processing for CD4+ T cells. 2. To determine the mechanism for alternate processing of M tuberculosis for MHC class I restricted CD8+ T cells, to determine if alternate antigen processing is modulated to the same degree and by the same factors as for MHC class II antigen processing and to determine roles of the 44 kDa Rv0341 and 71 kDa Rv3808c proteins as antigens for CD8+ T cells. 3. To determine the role of M tuberculosis phagosomes in Vdelta2+gamma delta T cell activation by phosphoantigens, to determine the sensitivity to inhibition by IL-10, TGF-B and 19 kDa lipoprotein of processing of M tuberculosis by mononuclear phagocytes for gamma/delta T cells; to determine mechanism of gamma/delta T cell mediated M tuberculosis growth inhibition.